This project is aimed at two closely related problems concerning man's adaptation to high altitude hypoxia: (1) The mechanisms which regulate the ionic composition of brain intra- and extra-cellular fluid ICF/ECF in long- term hypoxia, and (2) The role these regulatory factors play in mediating ventilatory acclimatization to hypoxia. In studies of brain ECF in hypoxia the writer has determined the regulation of CSF HCO3(-) movement between plasma and CSF, described the effects of hypoxia on brain P sub CO2 gradients, described the ventilatory response of the awake rat to steady-state ventricular-cisternal perfusion of various (H+), and--in man--has shown that the time-course of ventilatory 'de-acclimatization' from chronic hypoxia is not explained by changes in CSF (H+). Secondly, he has developed techniques for the study of brain intra-cellular pH and cerebral metabolism in dogs. Thirdly, he is well underway in his studies of brain neurotransmitters in hypoxia. That is, assays have been developed, control data has been obtained in many rats, the time- course of ventilatory acclimatization to chronic hypoxia in the awake rat has been described and he has completed initial studies of the affect of specific neurotransmitter blockade on the control of breathing in the awake animal.